IL29437A - Substituted piperidinoalkyl benzo (b)thiophenes and benzofurans - Google Patents
Substituted piperidinoalkyl benzo (b)thiophenes and benzofuransInfo
- Publication number
- IL29437A IL29437A IL29437A IL2943768A IL29437A IL 29437 A IL29437 A IL 29437A IL 29437 A IL29437 A IL 29437A IL 2943768 A IL2943768 A IL 2943768A IL 29437 A IL29437 A IL 29437A
- Authority
- IL
- Israel
- Prior art keywords
- compound
- piperidinol
- hydrogen
- thianaphthenyl
- chloro
- Prior art date
Links
- 150000001907 coumarones Chemical class 0.000 title claims description 5
- FCEHBMOGCRZNNI-UHFFFAOYSA-N 1-benzothiophene Chemical class C1=CC=C2SC=CC2=C1 FCEHBMOGCRZNNI-UHFFFAOYSA-N 0.000 title description 14
- 150000001875 compounds Chemical class 0.000 claims description 41
- -1 chloro, bromo, methyl Chemical group 0.000 claims description 26
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 26
- 239000001257 hydrogen Substances 0.000 claims description 23
- 229910052739 hydrogen Inorganic materials 0.000 claims description 23
- 239000002253 acid Substances 0.000 claims description 16
- QCQCHGYLTSGIGX-GHXANHINSA-N 4-[[(3ar,5ar,5br,7ar,9s,11ar,11br,13as)-5a,5b,8,8,11a-pentamethyl-3a-[(5-methylpyridine-3-carbonyl)amino]-2-oxo-1-propan-2-yl-4,5,6,7,7a,9,10,11,11b,12,13,13a-dodecahydro-3h-cyclopenta[a]chrysen-9-yl]oxy]-2,2-dimethyl-4-oxobutanoic acid Chemical compound N([C@@]12CC[C@@]3(C)[C@]4(C)CC[C@H]5C(C)(C)[C@@H](OC(=O)CC(C)(C)C(O)=O)CC[C@]5(C)[C@H]4CC[C@@H]3C1=C(C(C2)=O)C(C)C)C(=O)C1=CN=CC(C)=C1 QCQCHGYLTSGIGX-GHXANHINSA-N 0.000 claims description 15
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 13
- 125000001309 chloro group Chemical group Cl* 0.000 claims description 11
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 10
- 125000001153 fluoro group Chemical group F* 0.000 claims description 9
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical group [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims description 8
- 150000003839 salts Chemical class 0.000 claims description 8
- 239000011593 sulfur Chemical group 0.000 claims description 8
- 229910052717 sulfur Inorganic materials 0.000 claims description 8
- 125000004432 carbon atom Chemical group C* 0.000 claims description 6
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 6
- CVICEEPAFUYBJG-UHFFFAOYSA-N 5-chloro-2,2-difluoro-1,3-benzodioxole Chemical group C1=C(Cl)C=C2OC(F)(F)OC2=C1 CVICEEPAFUYBJG-UHFFFAOYSA-N 0.000 claims description 4
- 125000001589 carboacyl group Chemical group 0.000 claims description 4
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 4
- 150000003457 sulfones Chemical group 0.000 claims description 4
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 4
- 125000000217 alkyl group Chemical group 0.000 claims description 3
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 3
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 3
- 125000003545 alkoxy group Chemical group 0.000 claims description 2
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical group [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 2
- 125000001246 bromo group Chemical group Br* 0.000 claims description 2
- 229910052760 oxygen Inorganic materials 0.000 claims description 2
- 239000001301 oxygen Substances 0.000 claims description 2
- 150000002431 hydrogen Chemical class 0.000 claims 10
- 239000004480 active ingredient Substances 0.000 claims 1
- 125000005605 benzo group Chemical group 0.000 claims 1
- 239000008194 pharmaceutical composition Substances 0.000 claims 1
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 122
- 239000000243 solution Substances 0.000 description 65
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 55
- 239000000203 mixture Substances 0.000 description 49
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 42
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 36
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 25
- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 23
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 22
- 239000000047 product Substances 0.000 description 22
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 21
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 18
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 18
- 238000000034 method Methods 0.000 description 18
- 239000000284 extract Substances 0.000 description 16
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 15
- QTBSBXVTEAMEQO-UHFFFAOYSA-N acetic acid Substances CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 15
- OFOBLEOULBTSOW-UHFFFAOYSA-N Malonic acid Chemical compound OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 14
- 150000001408 amides Chemical class 0.000 description 14
- 239000010410 layer Substances 0.000 description 13
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 12
- LKPFBGKZCCBZDK-UHFFFAOYSA-N n-hydroxypiperidine Chemical compound ON1CCCCC1 LKPFBGKZCCBZDK-UHFFFAOYSA-N 0.000 description 12
- OFOBLEOULBTSOW-UHFFFAOYSA-L Malonate Chemical compound [O-]C(=O)CC([O-])=O OFOBLEOULBTSOW-UHFFFAOYSA-L 0.000 description 11
- 230000015572 biosynthetic process Effects 0.000 description 11
- 239000000706 filtrate Substances 0.000 description 11
- 235000019260 propionic acid Nutrition 0.000 description 11
- IUVKMZGDUIUOCP-BTNSXGMBSA-N quinbolone Chemical class O([C@H]1CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)CC[C@@]21C)C1=CCCC1 IUVKMZGDUIUOCP-BTNSXGMBSA-N 0.000 description 11
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 9
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 9
- RIFGWPKJUGCATF-UHFFFAOYSA-N ethyl chloroformate Chemical compound CCOC(Cl)=O RIFGWPKJUGCATF-UHFFFAOYSA-N 0.000 description 9
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 9
- 239000012258 stirred mixture Substances 0.000 description 9
- KQKFQBTWXOGINC-UHFFFAOYSA-N 4-phenylpiperidin-4-ol Chemical compound C=1C=CC=CC=1C1(O)CCNCC1 KQKFQBTWXOGINC-UHFFFAOYSA-N 0.000 description 8
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 8
- 239000007864 aqueous solution Substances 0.000 description 8
- LTMRRSWNXVJMBA-UHFFFAOYSA-L 2,2-diethylpropanedioate Chemical compound CCC(CC)(C([O-])=O)C([O-])=O LTMRRSWNXVJMBA-UHFFFAOYSA-L 0.000 description 7
- 229910000104 sodium hydride Inorganic materials 0.000 description 7
- 239000007787 solid Substances 0.000 description 7
- 239000007858 starting material Substances 0.000 description 7
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 6
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 6
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 6
- 229960000583 acetic acid Drugs 0.000 description 6
- 239000012259 ether extract Substances 0.000 description 6
- 239000012458 free base Substances 0.000 description 6
- 238000010438 heat treatment Methods 0.000 description 6
- HDOWRFHMPULYOA-UHFFFAOYSA-N piperidin-4-ol Chemical compound OC1CCNCC1 HDOWRFHMPULYOA-UHFFFAOYSA-N 0.000 description 6
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 6
- NGNBDVOYPDDBFK-UHFFFAOYSA-N 2-[2,4-di(pentan-2-yl)phenoxy]acetyl chloride Chemical compound CCCC(C)C1=CC=C(OCC(Cl)=O)C(C(C)CCC)=C1 NGNBDVOYPDDBFK-UHFFFAOYSA-N 0.000 description 5
- 230000002378 acidificating effect Effects 0.000 description 5
- 238000006243 chemical reaction Methods 0.000 description 5
- 125000004177 diethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 5
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 5
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 5
- 239000003921 oil Substances 0.000 description 5
- 239000003208 petroleum Substances 0.000 description 5
- 239000011541 reaction mixture Substances 0.000 description 5
- IANQTJSKSUMEQM-UHFFFAOYSA-N 1-benzofuran Chemical compound C1=CC=C2OC=CC2=C1 IANQTJSKSUMEQM-UHFFFAOYSA-N 0.000 description 4
- VBICKXHEKHSIBG-UHFFFAOYSA-N 1-monostearoylglycerol Chemical compound CCCCCCCCCCCCCCCCCC(=O)OCC(O)CO VBICKXHEKHSIBG-UHFFFAOYSA-N 0.000 description 4
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 4
- 239000002585 base Substances 0.000 description 4
- 238000006114 decarboxylation reaction Methods 0.000 description 4
- XXTZHYXQVWRADW-UHFFFAOYSA-N diazomethanone Chemical compound [N]N=C=O XXTZHYXQVWRADW-UHFFFAOYSA-N 0.000 description 4
- 239000000155 melt Substances 0.000 description 4
- 229910052757 nitrogen Inorganic materials 0.000 description 4
- NDVLTYZPCACLMA-UHFFFAOYSA-N silver oxide Chemical compound [O-2].[Ag+].[Ag+] NDVLTYZPCACLMA-UHFFFAOYSA-N 0.000 description 4
- 239000002904 solvent Substances 0.000 description 4
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 4
- WSFSSNUMVMOOMR-UHFFFAOYSA-N Formaldehyde Chemical compound O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 description 3
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 3
- PCLIMKBDDGJMGD-UHFFFAOYSA-N N-bromosuccinimide Chemical compound BrN1C(=O)CCC1=O PCLIMKBDDGJMGD-UHFFFAOYSA-N 0.000 description 3
- OSGAYBCDTDRGGQ-UHFFFAOYSA-L calcium sulfate Chemical compound [Ca+2].[O-]S([O-])(=O)=O OSGAYBCDTDRGGQ-UHFFFAOYSA-L 0.000 description 3
- DQYBDCGIPTYXML-UHFFFAOYSA-N ethoxyethane;hydrate Chemical compound O.CCOCC DQYBDCGIPTYXML-UHFFFAOYSA-N 0.000 description 3
- 125000004970 halomethyl group Chemical group 0.000 description 3
- 239000005457 ice water Substances 0.000 description 3
- 239000000543 intermediate Substances 0.000 description 3
- 239000007788 liquid Substances 0.000 description 3
- 239000012280 lithium aluminium hydride Substances 0.000 description 3
- 239000000463 material Substances 0.000 description 3
- 239000002480 mineral oil Substances 0.000 description 3
- 235000010446 mineral oil Nutrition 0.000 description 3
- 239000001788 mono and diglycerides of fatty acids Substances 0.000 description 3
- 239000006186 oral dosage form Substances 0.000 description 3
- 125000001501 propionyl group Chemical group O=C([*])C([H])([H])C([H])([H])[H] 0.000 description 3
- 238000001953 recrystallisation Methods 0.000 description 3
- 238000003756 stirring Methods 0.000 description 3
- 239000003826 tablet Substances 0.000 description 3
- 125000005306 thianaphthenyl group Chemical group 0.000 description 3
- RMVRSNDYEFQCLF-UHFFFAOYSA-N thiophenol Chemical class SC1=CC=CC=C1 RMVRSNDYEFQCLF-UHFFFAOYSA-N 0.000 description 3
- 230000002936 tranquilizing effect Effects 0.000 description 3
- 238000005406 washing Methods 0.000 description 3
- IZHVBANLECCAGF-UHFFFAOYSA-N 2-hydroxy-3-(octadecanoyloxy)propyl octadecanoate Chemical compound CCCCCCCCCCCCCCCCCC(=O)OCC(O)COC(=O)CCCCCCCCCCCCCCCCC IZHVBANLECCAGF-UHFFFAOYSA-N 0.000 description 2
- ZRXHLJNBNWVNIM-UHFFFAOYSA-N 3-methyl-1-benzofuran Chemical compound C1=CC=C2C(C)=COC2=C1 ZRXHLJNBNWVNIM-UHFFFAOYSA-N 0.000 description 2
- LZAYOZUFUAMFLD-UHFFFAOYSA-N 4-(4-chlorophenyl)-4-hydroxypiperidine Chemical compound C=1C=C(Cl)C=CC=1C1(O)CCNCC1 LZAYOZUFUAMFLD-UHFFFAOYSA-N 0.000 description 2
- DLFVBJFMPXGRIB-UHFFFAOYSA-N Acetamide Chemical compound CC(N)=O DLFVBJFMPXGRIB-UHFFFAOYSA-N 0.000 description 2
- FERIUCNNQQJTOY-UHFFFAOYSA-N Butyric acid Chemical compound CCCC(O)=O FERIUCNNQQJTOY-UHFFFAOYSA-N 0.000 description 2
- CURLTUGMZLYLDI-UHFFFAOYSA-N Carbon dioxide Chemical compound O=C=O CURLTUGMZLYLDI-UHFFFAOYSA-N 0.000 description 2
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
- YXHKONLOYHBTNS-UHFFFAOYSA-N Diazomethane Chemical compound C=[N+]=[N-] YXHKONLOYHBTNS-UHFFFAOYSA-N 0.000 description 2
- 108010010803 Gelatin Proteins 0.000 description 2
- MHAJPDPJQMAIIY-UHFFFAOYSA-N Hydrogen peroxide Chemical compound OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 0.000 description 2
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 2
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 2
- 241000700159 Rattus Species 0.000 description 2
- 238000010640 amide synthesis reaction Methods 0.000 description 2
- 239000002775 capsule Substances 0.000 description 2
- 239000003153 chemical reaction reagent Substances 0.000 description 2
- 239000012320 chlorinating reagent Substances 0.000 description 2
- 238000001035 drying Methods 0.000 description 2
- 238000001704 evaporation Methods 0.000 description 2
- 238000000605 extraction Methods 0.000 description 2
- 239000012467 final product Substances 0.000 description 2
- 239000008273 gelatin Substances 0.000 description 2
- 229920000159 gelatin Polymers 0.000 description 2
- 239000007903 gelatin capsule Substances 0.000 description 2
- 235000019322 gelatine Nutrition 0.000 description 2
- 235000011852 gelatine desserts Nutrition 0.000 description 2
- 239000012362 glacial acetic acid Substances 0.000 description 2
- 235000011187 glycerol Nutrition 0.000 description 2
- 229940075507 glyceryl monostearate Drugs 0.000 description 2
- 150000004820 halides Chemical class 0.000 description 2
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 2
- 239000008188 pellet Substances 0.000 description 2
- 239000000546 pharmaceutical excipient Substances 0.000 description 2
- 229940124531 pharmaceutical excipient Drugs 0.000 description 2
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 2
- UHZYTMXLRWXGPK-UHFFFAOYSA-N phosphorus pentachloride Chemical compound ClP(Cl)(Cl)(Cl)Cl UHZYTMXLRWXGPK-UHFFFAOYSA-N 0.000 description 2
- FAIAAWCVCHQXDN-UHFFFAOYSA-N phosphorus trichloride Chemical compound ClP(Cl)Cl FAIAAWCVCHQXDN-UHFFFAOYSA-N 0.000 description 2
- RZWZRACFZGVKFM-UHFFFAOYSA-N propanoyl chloride Chemical compound CCC(Cl)=O RZWZRACFZGVKFM-UHFFFAOYSA-N 0.000 description 2
- 229910001923 silver oxide Inorganic materials 0.000 description 2
- 239000002002 slurry Substances 0.000 description 2
- 239000011734 sodium Substances 0.000 description 2
- 229910052708 sodium Inorganic materials 0.000 description 2
- JIAARYAFYJHUJI-UHFFFAOYSA-L zinc dichloride Chemical compound [Cl-].[Cl-].[Zn+2] JIAARYAFYJHUJI-UHFFFAOYSA-L 0.000 description 2
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 1
- HSOMHPHYGAQRTF-UHFFFAOYSA-N 1-benzofuran-2-ylmethanol Chemical compound C1=CC=C2OC(CO)=CC2=C1 HSOMHPHYGAQRTF-UHFFFAOYSA-N 0.000 description 1
- MPPPKRYCTPRNTB-UHFFFAOYSA-N 1-bromobutane Chemical compound CCCCBr MPPPKRYCTPRNTB-UHFFFAOYSA-N 0.000 description 1
- IIZPXYDJLKNOIY-JXPKJXOSSA-N 1-palmitoyl-2-arachidonoyl-sn-glycero-3-phosphocholine Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@H](COP([O-])(=O)OCC[N+](C)(C)C)OC(=O)CCC\C=C/C\C=C/C\C=C/C\C=C/CCCCC IIZPXYDJLKNOIY-JXPKJXOSSA-N 0.000 description 1
- VFZQJKXVHYZXMM-UHFFFAOYSA-N 2-(1-benzothiophen-3-yl)acetic acid Chemical compound C1=CC=C2C(CC(=O)O)=CSC2=C1 VFZQJKXVHYZXMM-UHFFFAOYSA-N 0.000 description 1
- LSGCBNJHZGJEEJ-UHFFFAOYSA-N 2-(chloromethyl)-1-benzofuran Chemical compound C1=CC=C2OC(CCl)=CC2=C1 LSGCBNJHZGJEEJ-UHFFFAOYSA-N 0.000 description 1
- UXGVMFHEKMGWMA-UHFFFAOYSA-N 2-benzofuran Chemical compound C1=CC=CC2=COC=C21 UXGVMFHEKMGWMA-UHFFFAOYSA-N 0.000 description 1
- WDBPZYOUMCCOEO-UHFFFAOYSA-N 2-bromo-3-(bromomethyl)-1-benzofuran Chemical compound C1=CC=C2C(CBr)=C(Br)OC2=C1 WDBPZYOUMCCOEO-UHFFFAOYSA-N 0.000 description 1
- HTXWKZDRDRFVHN-UHFFFAOYSA-N 2-methyloxiran-2-ol Chemical compound CC1(O)CO1 HTXWKZDRDRFVHN-UHFFFAOYSA-N 0.000 description 1
- VSWICNJIUPRZIK-UHFFFAOYSA-N 2-piperideine Chemical class C1CNC=CC1 VSWICNJIUPRZIK-UHFFFAOYSA-N 0.000 description 1
- RSCSQNQHINMHDE-UHFFFAOYSA-N 3-(1-benzofuran-2-yl)propanoic acid Chemical compound C1=CC=C2OC(CCC(=O)O)=CC2=C1 RSCSQNQHINMHDE-UHFFFAOYSA-N 0.000 description 1
- SEBRPHZZSLCDRQ-UHFFFAOYSA-N 3-methyl-1-benzothiophene Chemical compound C1=CC=C2C(C)=CSC2=C1 SEBRPHZZSLCDRQ-UHFFFAOYSA-N 0.000 description 1
- IEMMIKLKEBDQLL-UHFFFAOYSA-N 4-(2-methylphenyl)piperidin-4-ol Chemical compound CC1=CC=CC=C1C1(O)CCNCC1 IEMMIKLKEBDQLL-UHFFFAOYSA-N 0.000 description 1
- SAYLAYXYGATQEB-UHFFFAOYSA-N 4-(3-bromophenyl)piperidin-4-ol Chemical compound C=1C=CC(Br)=CC=1C1(O)CCNCC1 SAYLAYXYGATQEB-UHFFFAOYSA-N 0.000 description 1
- QXWRXWPNHLIZBV-UHFFFAOYSA-N 4-(4-fluorophenyl)piperidin-4-ol Chemical compound C=1C=C(F)C=CC=1C1(O)CCNCC1 QXWRXWPNHLIZBV-UHFFFAOYSA-N 0.000 description 1
- 229920001817 Agar Polymers 0.000 description 1
- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 description 1
- 238000006218 Arndt-Eistert homologation reaction Methods 0.000 description 1
- 239000004342 Benzoyl peroxide Substances 0.000 description 1
- OMPJBNCRMGITSC-UHFFFAOYSA-N Benzoylperoxide Chemical compound C=1C=CC=CC=1C(=O)OOC(=O)C1=CC=CC=C1 OMPJBNCRMGITSC-UHFFFAOYSA-N 0.000 description 1
- KRKNYBCHXYNGOX-UHFFFAOYSA-K Citrate Chemical compound [O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O KRKNYBCHXYNGOX-UHFFFAOYSA-K 0.000 description 1
- 235000013162 Cocos nucifera Nutrition 0.000 description 1
- 244000060011 Cocos nucifera Species 0.000 description 1
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 1
- IYXGSMUGOJNHAZ-UHFFFAOYSA-N Ethyl malonate Chemical class CCOC(=O)CC(=O)OCC IYXGSMUGOJNHAZ-UHFFFAOYSA-N 0.000 description 1
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 description 1
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 1
- 240000007472 Leucaena leucocephala Species 0.000 description 1
- 235000010643 Leucaena leucocephala Nutrition 0.000 description 1
- 229910010084 LiAlH4 Inorganic materials 0.000 description 1
- WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 description 1
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 1
- 229910002651 NO3 Inorganic materials 0.000 description 1
- NHNBFGGVMKEFGY-UHFFFAOYSA-N Nitrate Chemical compound [O-][N+]([O-])=O NHNBFGGVMKEFGY-UHFFFAOYSA-N 0.000 description 1
- 229930040373 Paraformaldehyde Natural products 0.000 description 1
- YNPNZTXNASCQKK-UHFFFAOYSA-N Phenanthrene Natural products C1=CC=C2C3=CC=CC=C3C=CC2=C1 YNPNZTXNASCQKK-UHFFFAOYSA-N 0.000 description 1
- 239000007868 Raney catalyst Substances 0.000 description 1
- NPXOKRUENSOPAO-UHFFFAOYSA-N Raney nickel Chemical compound [Al].[Ni] NPXOKRUENSOPAO-UHFFFAOYSA-N 0.000 description 1
- 229910000564 Raney nickel Inorganic materials 0.000 description 1
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 1
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 1
- 229920002472 Starch Polymers 0.000 description 1
- 235000021355 Stearic acid Nutrition 0.000 description 1
- 229930006000 Sucrose Natural products 0.000 description 1
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 description 1
- 206010042618 Surgical procedure repeated Diseases 0.000 description 1
- 239000004809 Teflon Substances 0.000 description 1
- 229920006362 Teflon® Polymers 0.000 description 1
- YTPLMLYBLZKORZ-UHFFFAOYSA-N Thiophene Chemical compound C=1C=CSC=1 YTPLMLYBLZKORZ-UHFFFAOYSA-N 0.000 description 1
- JFBZPFYRPYOZCQ-UHFFFAOYSA-N [Li].[Al] Chemical compound [Li].[Al] JFBZPFYRPYOZCQ-UHFFFAOYSA-N 0.000 description 1
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- 150000001266 acyl halides Chemical class 0.000 description 1
- 239000008272 agar Substances 0.000 description 1
- 235000010419 agar Nutrition 0.000 description 1
- 230000001476 alcoholic effect Effects 0.000 description 1
- 239000003513 alkali Substances 0.000 description 1
- 229910052783 alkali metal Inorganic materials 0.000 description 1
- 150000008044 alkali metal hydroxides Chemical class 0.000 description 1
- 239000003708 ampul Substances 0.000 description 1
- 230000036592 analgesia Effects 0.000 description 1
- 230000000202 analgesic effect Effects 0.000 description 1
- 229940035676 analgesics Drugs 0.000 description 1
- 150000008064 anhydrides Chemical class 0.000 description 1
- 239000000730 antalgic agent Substances 0.000 description 1
- 239000006286 aqueous extract Substances 0.000 description 1
- 125000003118 aryl group Chemical group 0.000 description 1
- 125000000499 benzofuranyl group Chemical group O1C(=CC2=C1C=CC=C2)* 0.000 description 1
- 235000019400 benzoyl peroxide Nutrition 0.000 description 1
- 238000009835 boiling Methods 0.000 description 1
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 1
- 229910052794 bromium Inorganic materials 0.000 description 1
- 125000005997 bromomethyl group Chemical group 0.000 description 1
- 244000309464 bull Species 0.000 description 1
- DVECBJCOGJRVPX-UHFFFAOYSA-N butyryl chloride Chemical compound CCCC(Cl)=O DVECBJCOGJRVPX-UHFFFAOYSA-N 0.000 description 1
- 239000001506 calcium phosphate Substances 0.000 description 1
- 229910000389 calcium phosphate Inorganic materials 0.000 description 1
- 235000011010 calcium phosphates Nutrition 0.000 description 1
- 239000001569 carbon dioxide Substances 0.000 description 1
- 229910002092 carbon dioxide Inorganic materials 0.000 description 1
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 1
- 150000001735 carboxylic acids Chemical class 0.000 description 1
- 239000000969 carrier Substances 0.000 description 1
- 239000003054 catalyst Substances 0.000 description 1
- 230000003197 catalytic effect Effects 0.000 description 1
- KXZJHVJKXJLBKO-UHFFFAOYSA-N chembl1408157 Chemical compound N=1C2=CC=CC=C2C(C(=O)O)=CC=1C1=CC=C(O)C=C1 KXZJHVJKXJLBKO-UHFFFAOYSA-N 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 238000005660 chlorination reaction Methods 0.000 description 1
- BULLHNJGPPOUOX-UHFFFAOYSA-N chloroacetone Chemical compound CC(=O)CCl BULLHNJGPPOUOX-UHFFFAOYSA-N 0.000 description 1
- 125000004218 chloromethyl group Chemical group [H]C([H])(Cl)* 0.000 description 1
- 238000009833 condensation Methods 0.000 description 1
- 230000005494 condensation Effects 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 239000012024 dehydrating agents Substances 0.000 description 1
- NPOMSUOUAZCMBL-UHFFFAOYSA-N dichloromethane;ethoxyethane Chemical compound ClCCl.CCOCC NPOMSUOUAZCMBL-UHFFFAOYSA-N 0.000 description 1
- 235000014113 dietary fatty acids Nutrition 0.000 description 1
- YWEUIGNSBFLMFL-UHFFFAOYSA-N diphosphonate Chemical compound O=P(=O)OP(=O)=O YWEUIGNSBFLMFL-UHFFFAOYSA-N 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- AFAXGSQYZLGZPG-UHFFFAOYSA-L ethane-1,2-disulfonate Chemical compound [O-]S(=O)(=O)CCS([O-])(=O)=O AFAXGSQYZLGZPG-UHFFFAOYSA-L 0.000 description 1
- LBAQSKZHMLAFHH-UHFFFAOYSA-N ethoxyethane;hydron;chloride Chemical compound Cl.CCOCC LBAQSKZHMLAFHH-UHFFFAOYSA-N 0.000 description 1
- OAYLNYINCPYISS-UHFFFAOYSA-N ethyl acetate;hexane Chemical compound CCCCCC.CCOC(C)=O OAYLNYINCPYISS-UHFFFAOYSA-N 0.000 description 1
- 239000000194 fatty acid Substances 0.000 description 1
- 229930195729 fatty acid Natural products 0.000 description 1
- 150000004665 fatty acids Chemical class 0.000 description 1
- 239000012065 filter cake Substances 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 238000005755 formation reaction Methods 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- 238000007429 general method Methods 0.000 description 1
- 229940074045 glyceryl distearate Drugs 0.000 description 1
- 239000008187 granular material Substances 0.000 description 1
- 230000002140 halogenating effect Effects 0.000 description 1
- YWGHUJQYGPDNKT-UHFFFAOYSA-N hexanoyl chloride Chemical compound CCCCCC(Cl)=O YWGHUJQYGPDNKT-UHFFFAOYSA-N 0.000 description 1
- 150000004678 hydrides Chemical class 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 230000003301 hydrolyzing effect Effects 0.000 description 1
- 150000002440 hydroxy compounds Chemical class 0.000 description 1
- 125000004029 hydroxymethyl group Chemical group [H]OC([H])([H])* 0.000 description 1
- 239000007972 injectable composition Substances 0.000 description 1
- 229940102223 injectable solution Drugs 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- 239000000787 lecithin Substances 0.000 description 1
- 235000010445 lecithin Nutrition 0.000 description 1
- 229940067606 lecithin Drugs 0.000 description 1
- 239000012669 liquid formulation Substances 0.000 description 1
- 229910052744 lithium Inorganic materials 0.000 description 1
- 239000007937 lozenge Substances 0.000 description 1
- 239000000395 magnesium oxide Substances 0.000 description 1
- 229960000869 magnesium oxide Drugs 0.000 description 1
- CPLXHLVBOLITMK-UHFFFAOYSA-N magnesium oxide Inorganic materials [Mg]=O CPLXHLVBOLITMK-UHFFFAOYSA-N 0.000 description 1
- 235000019359 magnesium stearate Nutrition 0.000 description 1
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 1
- 229910000403 monosodium phosphate Inorganic materials 0.000 description 1
- 235000019799 monosodium phosphate Nutrition 0.000 description 1
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 1
- OQCDKBAXFALNLD-UHFFFAOYSA-N octadecanoic acid Natural products CCCCCCCC(C)CCCCCCCCC(O)=O OQCDKBAXFALNLD-UHFFFAOYSA-N 0.000 description 1
- 239000012044 organic layer Substances 0.000 description 1
- 230000001590 oxidative effect Effects 0.000 description 1
- 229920002866 paraformaldehyde Polymers 0.000 description 1
- 239000001814 pectin Substances 0.000 description 1
- 235000010987 pectin Nutrition 0.000 description 1
- 229920001277 pectin Polymers 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- DLYUQMMRRRQYAE-UHFFFAOYSA-N phosphorus pentoxide Inorganic materials O1P(O2)(=O)OP3(=O)OP1(=O)OP2(=O)O3 DLYUQMMRRRQYAE-UHFFFAOYSA-N 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 238000002360 preparation method Methods 0.000 description 1
- 239000003755 preservative agent Substances 0.000 description 1
- QLNJFJADRCOGBJ-UHFFFAOYSA-N propionamide Chemical compound CCC(N)=O QLNJFJADRCOGBJ-UHFFFAOYSA-N 0.000 description 1
- 229940080818 propionamide Drugs 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 239000012266 salt solution Substances 0.000 description 1
- 230000001624 sedative effect Effects 0.000 description 1
- HELHAJAZNSDZJO-OLXYHTOASA-L sodium L-tartrate Chemical compound [Na+].[Na+].[O-]C(=O)[C@H](O)[C@@H](O)C([O-])=O HELHAJAZNSDZJO-OLXYHTOASA-L 0.000 description 1
- QDRKDTQENPPHOJ-UHFFFAOYSA-N sodium ethoxide Chemical compound [Na+].CC[O-] QDRKDTQENPPHOJ-UHFFFAOYSA-N 0.000 description 1
- 239000012312 sodium hydride Substances 0.000 description 1
- 239000001433 sodium tartrate Substances 0.000 description 1
- 229960002167 sodium tartrate Drugs 0.000 description 1
- 235000011004 sodium tartrates Nutrition 0.000 description 1
- 238000010561 standard procedure Methods 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 239000008117 stearic acid Substances 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 239000005720 sucrose Substances 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- 235000012222 talc Nutrition 0.000 description 1
- 229940095064 tartrate Drugs 0.000 description 1
- RTKIYNMVFMVABJ-UHFFFAOYSA-L thimerosal Chemical compound [Na+].CC[Hg]SC1=CC=CC=C1C([O-])=O RTKIYNMVFMVABJ-UHFFFAOYSA-L 0.000 description 1
- 229930192474 thiophene Natural products 0.000 description 1
- 239000003204 tranquilizing agent Substances 0.000 description 1
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 1
- QORWJWZARLRLPR-UHFFFAOYSA-H tricalcium bis(phosphate) Chemical compound [Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O QORWJWZARLRLPR-UHFFFAOYSA-H 0.000 description 1
- 238000001665 trituration Methods 0.000 description 1
- 239000011592 zinc chloride Substances 0.000 description 1
- 235000005074 zinc chloride Nutrition 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
- A61K31/443—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with oxygen as a ring hetero atom
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
- A61K31/4436—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a heterocyclic ring having sulfur as a ring hetero atom
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
- C07D405/06—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
- C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
- C07D409/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
- Hydrogenated Pyridines (AREA)
Description
SUBSTITUTED PIPEHIDINOAI YL BEMZO (b) THIOPHENES ATJD BEIZOFURANS This invention relates to thianaphthene and benzofuran compounds having pharmacological activity. In particular, the invention relates to 4=aryl°4-hydroxypiperidino« alkyl derivatives of thianaphthenes and benzofurans having tranquilizing and analgesic activity.
The compounds of the invention are represented by the following structural formula; R is hydrogen, chloro, bromo, fluoro, trifluoromethyl lower alkyl of up to about 4 carbon atoms, or lower alkoxy of up to about 4 carbon atoms; R is hydrogen, chloro, bromo, methyl, trifluoromethyl, fluoro, or methoxy; 2 R is hydrogen or methyl; 3 R is hydrogen or lower alkanoyl of up to 6 carbon atoms ; Y is sulfur, sulfone, or oxygen; and n is a positive integer from 2 to 4.
Also part of the invention are the pharmaceutically acceptable acid addition salts of the compounds of formula I. Among these salts are the hydrochloride, hydrobromide, sulfate, nitrate, maleate, tartrate, citrate, or ethane disulfonate.
Among the preferred groups of compounds are those where R is hydrogen, chloro, and fluoro and is at the 5 or 6- 1 position; R is hydrogen, chloro, or fluoro and is at the The compounds aocording to the present invention are prepared via intermediates of the , following structural formula! d above.
The compounds of the invention are prepared by various methods which are hereinbelow described* They involve condensation of a 4-phenyl-4-piperidinol with a derivative of an optionally substituted benzofuran- or thianaphthenealkanoic acid. Such derivatives may be an ester anhydride with ethyl chloroformate, an acl'd halide, or a diazo ketone. 2 The compounds of the invention where n is 3 and R is hydrogen are preferably prepared according to the procedures illustrated schematically below: 3-halomethylthianaphthene or benzofuran (III) is condensed with diethyl malonate in the presence of a base such as sodium ethoxide or sodium hydride to give a substituted malonic ester, which is then hydrolyzed with aqueous alkali to give the malonic acid IV. Decarboxylation by heating at about 200-250° results in the formation of a substituted propionic acid (V), which is then condensed with ethyl chloroformate to give an ester anhydride (VI). Reaction with a 4-phenyl-4-piperidinol results in the formation of an intermediate amide (Ila). Reduction of this amide with a reagent such as lithium aluminum hydride in ether or tetra-hydrofuran gives the final product, Ia. The final product is converted to an acid addition salt by bringing together the free base, which may be dissolved in a solvent such as ether, alcohol, or acetone with the acid, which also may be in solution. A preferred method of salt formation involves the addition of ethereal hydrogenchloride to an ether solution of the free base. literature or are prepared from known materials by means of published methods. For example thianaphthene-3°propionic acid is described in Bull. soc. chim. France 1953» 185=90 ; 2-chloromethylthianaphthene is described in J. Am. Chem. Soc. 71, 2857 (1949) 2-chloromethylbenzofuran is described in J. Am. Chem. Soc. 73, 4400 (1951) ; 3°chloromethy 1thianaphthene is described in J. Chem. Soc. 1961, 1291=7 ; general methods for preparing substituted 2 or 3-halomethylthianaphthenes and benzofurans are described in U. S. Patent 3* 070, 606.
The 3-halomethylthianaphthene starting materials are conveniently prepared from substituted thiophenols, as follows.
The substituted thiophenol is dissolved in an aqueous solution containing an equivalent amount of an alkali metal hydroxide, such as sodium :· or potassium hydroxide, and x i treated with an equivalent amount of chloroacetone at about -25° for 20 to 60 minutes. The reaction mixture is diluted with a water-immiscible solvent such as ether. The organic layer is separated* solvent evaporated and the residue distilled in vacuo to obtain the l-phenylnairaapft@p2°propanone. This propanone is cyclized by heating at 160-180° for 30-45 minutes with a dehydrating agent, such as zinc chloride or, preferably, phosphorus pentoxide, to obtain the 3-methylthianaphthene, which is then treated with a halogenating agent such as, preferably, N=bromosuccinimide to give the 3=bromomethyl= thianaphthene.
The 2°halomethylthianaphthene starting materials are prepared as follows % An ether solution of the thianaphthene is added to an ether solution containing lithium and butyl bromide, butyl lithium being present in about a four-fold excess, and the mixture refluxed for one to two hours. Approximately a four solution over a period of three to five hours. Water and a lower alcohol, such as ethanol, are added; the mixture is made acidic with hydrochloric acid; the ether layer is separated and evaporated to obtain the 2-hydroxymethylthianaphthene as the residue, which is purified by recrystallization from a suitable solvent, such as n-heptane. Reaction of the hydroxymethyl compound with a chlorinating agent, such as phosphorus trichloride, phosphorus pentachloride or, preferably, thionyl chloride, yields the starting material, 2-chloromethyl-thianaphthene.
A 3-halomethylbenzofuran starting material is conveniently prepared by bromlnation of a 3-methylbenzofuran with at least two molar equivalents of N-bromosuccinimide in the presence of a catalytic amount of benzoyl peroxide to give the 2-bromo-3-bromomethylbenzofuran which is then treated as outlined previously, except that at some point during the reaction sequence, preferably after the decarboxylation, the 2-bromo-3-propionic acid is hydrogenated in the presence of a catalyst such as Raney nickel to remove the 2.-bromine.
The 2-halomethylbenzofuran starting materials are prepared from a coumarillc acid by reduction with a bimetallic hydride such as lithium aluminum hydride and chlorination of the resulting 2-hydroxymethylbenzofuran with a chlorinating agent such as phosphorus pentachloride, phosphorus trichloride or, preferably, thionyl chloride.
The compounds of the invention wherein n is 2 are preferably prepared by condensing the acid halide of a thianaphthene or benzofuran-2- or 3-acetic acid with the appropriate 4-phenyl-4-piperidinol to give the acetamide, and this amide reduced with a reagent such as lithium aluminum thlanaphthene or benzofuran with an alkali metal cyanide such as sodium cyanide, and then hydrolyzing the resulting acetonitrile with a base such as aqueous potassium hydroxide.
The compounds of the invention wherein n is 4 are preferably prepared by homologating the corresponding propionic acid intermediates through the use of the Arndt-Eistert reaction. The acid is converted to its acid hallde, condensed with diazomethane, and the resulting diazoketone treated with a 4=phenyl=4»piperidinol in the presence of silver oxide to give an amide , which is reduced in the conventional manner to the product. Alternatively, the diazoketone is hydrolyzed with aqueous silver oxide to the butyric acid, which is then converted via its acid chloride to the 4°phenylpiperidine amide, and the amide reduced to the product in the customary manner. 2 The various product compounds wherein R is methyl are generally prepared from the known carboxylic acids or halomethyl compounds possessing the methyl group. A further method for preparing 2 or 3=halomethyl compounds having a 2 or 3-methyl group involves reaction of a chloromethyl compound with magnesium and carbon dioxide [J. Am. Chem. Soc. 74, 766 (1952)3 to give the methyl carboxylic acid, and subsequent conversion by disclosed methods of the carboxy group to the halomethyl and then to the higher alkanoic acids . 3 The compounds of the invention in which R is lower alkanoyl are prepared by acylating the corresponding hydroxy compound in the conventional manner with an anhydride or acyl halide such as acetic anhydride, propionyl chloride, butyryl chloride, or hexanoyl chloride. ' -ptpertdtnela with rofluxing concentrated hydrochloric aeid.
Compounds in which Y is sulfone are prepared by oxidizing the corresponding thlanaphthene in which Y is sulfur with 30% hydrogen peroxide and glacial acetic acid.
The piperidinol compounds (R =H) of formula I and the tetrahydropyridine compounds of formula lib are tranquilizers. They have been found to cause a tranquilizing or sedative effect in rats when administered in oral doses of 200 mg/kg. They are formulated for use by combining them in amounts of 1°500 mg„ with standard pharmaceutical excipients into solid and liquid oral dosage forms and injectables by methods well known to pharmaceutical chemists. 3 The ester compounds (R = alkanoyl) of formula I are analgesics. They have been found to produce analgesia in rats in oral doses of 10-25 mg/kg. They are formulated for use by combining them in amounts of 1°250 nag. with standard pharmaceutical excipients into solid and liquid oral dosage forms and injectables by methods similarly well known to pharmaceutical chemists.
Oral dosage forms may be in the form of tablets, capsules, troches, or lozenges. In a tablet, the active component is generally incorporated into a solid carrier.
Among the acceptable solid carriers are lactose, sucrose, magnesium stearate, stearic acid, starchy terra alba, talc, calcium phosphate, gelatin, agar, pectin, and acacia. A time- delay material such as glyceryl monostearate or glyceryl distearate, alone or with a wax, may also be included. A capsule may be prepared by placing the active component, either alone or incorporated into a solid carrier, in a hard gelatin capsule. A liquid formulation may consist of the active component suspended or dissolved in a liquid carrier such as formulation may be consumed orally as such, included in a soft gelatin capsule, or placed in an ampule. An injectable formulation may consist of a solution of the active component in normal saline solution, water, or sugar solution, possibly with preservatives such as Merthiolate or parabens added.
Suppositories may also be prepared, containing 1-50 mg. of active compound and such components as glycerin, glycerin monopalm ate, glyceryl monostearate, hydrogenated cocoanut oil fatty acids, and lecithin.
The following examples are intended to illustrate the preparation of the compounds of the invention, but are not « to be construed as limiting the scope thereof.
EXAMPLE 1 1- [ 3- (5-Chloro°2°thianaphthenyl)propyl] °4°phenyl°4°piperidinol To a stirred mixture of 5.38 g. of 56.1% NaH in mineral oil (0.125 moles of NaH) in 75 ml. of dimethyl sulfoxide is added dropwise 20.1 g. (0.125 moles) of diethyl malonate in 20 ml. of dimethyl sulfoxide. The mixture is stirred in a hot water bath for a half hour, cooled to room temperature, and a solution of 13.67 g. (0.063 moles) of 5-chloro-2-chloromethylthianaphthene in 50 ml. of dimethyl sulfoxide added. The mixture is stirred on the steam bath for 1 hour, cooled, and poured into water. The mixture is then extracted with ether, and the ethereal extracts washed, dried, and evaporated. The residue is dissolved in acetonitrile, washed with petroleum ether, the petroleum ether solution washed with acetonitrile, and the combined acetonitrile solutions evaporated. The residue is distilled, the distillate up to 180°/0.5 mm. being discarded. The product diethyl (5-chloro»2-thianaphthenylmethyl)malonate A mixture of 8.3 g. (0,0244 moles) of the above malonate, 9.5 g. of KOH, 15 ml. of water, and 100 ml. of alcohol are refluxed with stirring overnight. The mixture is diluted with water and concentrated in vacuo to remove the alcohol. The residue is then diluted with water and ether, and the layers separated. The aqueous solution is washed with ether, the ether washed with water; the aqueous solution is acidified with HC1 and extracted with ether. The ethereal extracts are dried and evaporated to give the (5=chloro°2= thianaphthenylmethyl)malonic acid, m.p. 194-196°.
The above malonic acid (6.5 g., 0.0229 moles) is heated in an oil bath to 240°, and kept at 210-230° for 1 hour. The resulting 3-(5-chloro-2-thianaphthenyl)propionic acid, when cooled, solidifies and melts at 135-145 .
To a solution of this propionic acid in 25 ml. of acetone is added a solution of 4.1 g. (0.04 moles) of triethylamine in 10 ml. of acetone. The solution is cooled to -10° and a solution of 4.35 g. (0.04 moles) of ethyl chloro-formate in 10 ml. of acetone is added dropwise. The resulting solution is stirred in a salt-ice bath for 10 minutes and allowed to warm to room temperature, arid a slurry of 9.2 g. (0.052 moles) of 4-phenyl-4°piperidinol in 60 ml. of acetone is added. The resulting mixture is stirred and refluxed for 2 hours and poured into water and ether. The layers are separated, the aqueous solution is washed with ether, and the combined ether extracts are washed, dried, and evaporated to give 1- [3- (5-chloro=2=thianaphtheny1)propionyl] -4-phenyl-4» piperidinol, recrystallized from ethyl acetate-hexane, m.p. 123-126°.
To a stirred mixture of 4.5 g. of LiAlH^ in 600 ml. of dr ether is added a solution of 9.1 . 0.0227 moles of of dry ether. The resulting mixture is stirred and refluxed for 2 hours, and water and 10% NaOH are added dropwise. The mixture is then filtered, the ethereal filtrate washed and extracted with dilute HC1 and water, and the combined aqueous extracts made basic with NaOH. Extraction with ether, and washing, drying, and evaporating the ether extracts gives the title product. The compound is dissolved in alcohol, ethereal HC1 is added, and the hydrochloride salt is filtered off and recrystallized from alcohol~ethe ; m.p. 218-220°.
EXAMPLE 2 4-Phenyl-l-[3-(3-thianaphthenyl)propyl]°4°piperidinol To a mixture of 4.12 g. (0.02 moles) of 3-(3= thianaphthenyl)propionic acid in 20 ml. of acetone and 4 ml. of water is added 3.6 g. (0.035 moles) of triethylamine in 10 ml. of acetone. The solution is cooled to =>10° and a solution of 3.8 g. (0.035 moles) of ethyl chloroformate in 10 ml. of acetone is added dropwise. The resulting solution is stirred for 5 minutes at -10°, allowed to warm to room temperature, and 8.03 g. (0.0454 moles) of 4-phenyl-4-piperidinol in 50 ml. of acetone added. The resulting mixture is refluxed for 2 hours and allowed to stand for 2 days. The resulting white precipitate of the hydrochloride of the starting piperidinol is filtered off, the filtrate is evaporated in vacuo and triturated with methylene chloride, and the mixture again filtered. The filtrate is washed, dried, and evaporated and the residue of 4-phenyl-l-[3«(3=thianaphthenyl)propionyl]°4-piperidinol recrystallized by dissolving in hot ethyl acetate and reprecipitating with hexane; m.p. 94-98°.
To a stirred mixture of 2.0 g. of LiAlH^ in 200 ml. of dry ether is added 5.0 g. (0.0137 moles) of the above amide in 400 ml. of dr ether. The resultin mixture is stirred temperature. The mixture is then refluxed for a further 4 hours, water and 10% NaOH are added dropwise, and the mixture is filtered. The filtrate is washed with water and extracted with dilute HC1, and the combined aqueous solutions basified with NaOH. Extraction with ether-methylene chloride, and washing, drying, and evaporating the organic extracts gives the title product, m.p. 107-110°. The basic product is then dissolved in warm alcohol and filtered, and ethereal HC1 added to the filtrate. The resulting hydrochloride salt is recrystallized from alcohol-ether and melts at 209=211°.
EXAMPLE 3 4-Pheny1-1-13-(2-thianaphthenyppropyl] °4°piperidinol To 250 ml. of absolute alcohol is added 4.6 g. (0.2 moles) of sodium cut into pieces. This mixture is stirred for one-half hour and 35.3 g. (0.22 moles) of diethyl malonate is then added. The mixture is then stirred and refluxed for 2 hours and a solution of 1.82 g. (0.1 moles) of 2-chloromethylthianaphthene in 90 ml. of dry ether is added. The ether is boiled off and the remaining solution is refluxed overnight. The reaction mixture is poured into ice water and extracted with ether. The ether extracts are washed, dried, and evaporated, and the residue is distilled. The forerun distilling up to 170°/0.5 mm. is discarded. The fraction boiling at 170-176°/0.5 mm. is collected and is diethyl (2-thianaphthenylmethy1)malonate.
A solution of 11.0 g. (0.0359 moles) of the above malonate and 15 g. of K0H in 500 ml. of ethanol and 50 ml. of water is refluxed with stirring for 4 hours and then evaporated in vacuo. The residue is dissolved in water, washed with ether, the ether washings being then washed with water, and the dried, and evaporated to give (2-thianaphthenylmethyl)malonic acid, m.p. 181-183°.
The above malonic acid (7.6 g., 0.031 moles) is heated in an oil bath at 230-250° for one-half hour and the melt is cooled to give 3-(2-thianaphthenyl)propionic acid.
To a solution of this acid in 34 ml. of acetone is added a solution of 5.55 g. (0.0542 moles) of triethy1amine in 13.5 ml. of acetone. The resulting solution is stirred in a salt-ice bath at -10-0° while a solution of 5.89 g. (0.0542 moles) of ethyl chloroformate in 13.5 ml. of acetone is added dropwise. The mixture is then stirred in ice for 10 minutes, allowed to warm to room temperature, and an additional 80 ml. of acetone added, followed by 12.45 g. (0.0704 moles) of 4-phenyl-4-piperidinol. The reaction mixture is refluxed for 2 hours, allowed to stand overnight at room temperature, and then poured into ether-water. The layers are separated, the aqueous layer washed with ether, and the combined ether extracts washed successively with water, dilute HC1, water, dilute NaOH, and water. When the ether solution is dried and evaporated, 4-phenyl-l-[ 3-(2-thianaphthenyl)propionyl] -4-piperidinol is obtained.
To a stirred mixture of 6.0 g. of LiAlH^ in 800 ml. of dry ether is added a solution of 11.31 g. (0.031 moles) of the above amide in 80 ml. of dry tetrahydrofuran. The resulting mixture is refluxed for 3 hours and allowed to stand overnight at room temperature, and 25 ml. of water and 6 ml. of 10% NaOH added dropwise. The mixture is then stirred for one-half hour and filtered, and the filtrate washed with water and extracted with dilute HC1. The acidic extracts are basified with 40 NaOH and extracted with ether. The ether HCl added to give the hydrochloride salt of the product.
Recrystallization is achieved using alcohol-ether; m.p. 209-211°.
EXAMPLE 4 1-[3-(2-Benzofurany1)propyl1-4-phenyl-4-piperidinol To a stirred mixture of 19.2 g. of 56.1% NaH in mineral oil (10.7 g., 0.444 moles of NaH) in 265 ml. of dimethyl sulfoxide is added dropwise a solution of 7.15 g. (0.444 moles) of diethyl malonate in 70 ml. of dimethyl sulfoxide. The mixture is then stirred in a hot water bath for 1 hour and cooled to room temperature. A solution of 37.3 g. (0.224 moles) of 2-chlorometh lbenzofuran in 150 ml. of dimethyl sulfoxide is added dropwise, the mixture is refluxed with stirring for 1 hour, and is then poured into water-ether. The layers are separated, the aqueous solution is washed with ether, and the combined ether extracts are washed, dried and evaporated in vacuo. The residue is dissolved in acetonitrile and washed with petroleum ether, the petroleum ether solution extracted with acetonitrile, and the combined acetonitrile extracts evaporated in vacuo. The residue is distilled through a silvered column and the material distilling at 143°/0.5 mm. collected. This compound is diethyl (2-benzofuran Imethyl)malonate.
A mixture of 31.9 g. of 0H in 50 ml. of water and 31.9 g. (0.11 moles) of this malonate ester in 500 ml. of alcohol is stirred and refluxed for 3 hours and then evaporated in vacuo. The residue is dissolved in water and the aqueous solution washed with ether and acidified with concentrated HCl. The acid solution is extracted with ether and the ethereal extracts washed, dried, and evaporated to give (2-benzofuranylmethyl)malonic acid, m.p. 171-172°. 3-(2-benzofuranyl)propionic acid, m.p. 109-112°. This compound is dissolved in 40 ml. of acetone and 6.7 g. (0.0653 moles) of trieth lamine in 16 ml. of acetone is added. The solution is cooled in salt-ice to 0-10° and a solution of 7.1 g. (0.0653 moles) of ethyl chloroformate in 16 ml. of acetone added dropwise. The resulting mixture is stirred with cooling for 10 minutes and allowed to warm to room temperature, after which a slurry of 15.0 g. (0.0849 moles) of 4-phenyl-4-piperidinol in 100 ml. of acetone is added. The mixture is stirred at reflux for 2 hours, allowed to stand overnight at room temperature, refluxed for an additional hour and a half, and then poured into water-ether. The layers are separated, the aqueous layer extracted with ether, and the combined ethereal solutions washed, dried, and evaporated in vacuo to give as a gum, 4-phenyl-l-[3-(2-benzofuranyl)propionyl]-4-piperidinol, which when ether is added solidifies; m.p. 103-105 To a stirred mixture of 7.5 g. of LiAlH^ in 300 ml. of dry ether is slowly added a solution of 0.0374 moles of the above amide in 60 ml. of dry tetrahydrofuran and 600 ml. of dry ether. The mixture is stirred and refluxed for 3 hours, allowed to stand at room temperature overnight, and then ml. of water and 7.5 ml. of 10% NaOH cautiously added. The mixture is filtered, the filter cake being washed well with tetrahydrofuran, and the combined organic extracts extracted with dilute HC1. The acidic extracts are made basic with 40% NaOH, extracted with ether, and the ethereal extracts washed, dried, and evaporated in vacuo to give the title product. A hydrochloride salt is formed by adding to an alcoholic solution of the free base ethereal HC1 and recrystallizing from alcohol-ether; m.p. 148-151°.
EXAMPLE 5 1- [ 3- (3-Benzofuranyl)propyl 1 -4-phenyl-»4-piperidinol The procedures of Examples 1, 3 or 4 are followed. 3-ChloromeChylbenzofuran is condensed with malonate to give diethyl (3-benzofuranylmethyl)malonate. The malonate is hydrolyzed to the diacid with aqueous KOH, monodecarboxylated by heating, ethyl chloroformate is added to the triethylamine salt of the resulting propionic acid, and 4-phenyl-4-piperidinol added to the resulting ester anhydride to give a proplonamide . The amide is reduced to the product with LiAlH4.
EXAMPLE 6 4-p-Chlorophenyl-l- [ 3- (3-thianaphthenyppropyl ] -4-piperidinol The procedure of Example 2 is followed. 3- (3-Thianaphthenyl)propionic acid is converted to its triethylamine salt and then the salt allowed to react with ethyl chloro-formate. The resulting ester anhydride is condensed with 4-p-chlorophenyl=4-piperidinol to give an amide, which is reduced with LiAlH^ to give the product.
Use of 4-p-tolyl-4~piperidinol or 4-p-trifluoro-methylphenyl-4-piperidinol in the above procedure instead of 4-p-chlorophenyl-4-piperidinol results in the formation of 1- [ 3- (3-thianaphthenyl)propyl] -4-p-tolyl-4-piperidinol or 1- [ 3- (3-thianaphthenyppropyl] -4-p-trifluoromethylphenyl-4-piperidinol, respectively.
Use of 4-m-bromophenyl-4-piperidinol or 4- o-tolyl-4-piperidinol in the above procedure instead of 4-p-chlorophenyl-4-piperidinol results in the formation of 4-m-bromophenyl-l-[3-(3-thianaphthenyl)propyl]-4-piperidinol or l-[3-(3-thianaphthenyl)propyl]-4-o-tolyl-4-piperidinol, respectively.
Use of fluoro or methox substituted hen l- EXAMPLE 7 4-p-Chlorophenyl-l-[3-(6-fluoro-3-thianaphthenyl)propyl] -4-plperidinol The procedures of Examples 1, 3, or 4 are followed. 6-Fluoro-3-chloromethylthianaphthene is condensed with sodtfS111 diethyl malonate to give diethyl (6-fluoro-3-thianaphthenyl-methyl)malonate. The malonate is hydrolyzed to the diacid with aqueous KOH, the diacid monodecarboxylated by heating, ethyl chloroformate is added to the trie h lamine salt of the resulting propionic acid, and 4-p-chlorophenyl°4-piperidinol added to the resulting ester anhydride to give a propionamide. Reduction of the amide with LiAlH^ gives the product.
Use of 6-chloro-3-chloromethylthianaphthene as starting material instead of 6-fluoro-3-cbloromethyl-thianaphthene results in the formation of 4-p-chlorophenyl-l- [3-(6-chloro-3-thianaphthenyl)propyl] -4-piperidinol.
Use of 6-trifluoromethyl-3-chloromethylthianaphthene, -methyl-3-chloromethylthianaphthene, 5-butyl-2-chloromethyl-thianaphthene, 6-bromo=3-chloromethylbenzofuran, 6-methoxy-2-chloromethylthianaphthene, or 6-butoxy-2-chloromethylbenzo-furan as starting material instead of 6-fluoro-3-chloromethyl-thianaphthene results in the formation of 4-p-chlorophenyl-l- [3-(6-trifluoromethyl-3-thianaphthenyl)propyl] -4-piperidinol, 4-p-chlorophenyl-l-[3-(5-methyl-3-thianaphthenyl)propyl] -4-piperidinol, l-[3-(5-butyl-2-thianaphthenyl)propyl]-4-p-chlorophenyl-4-piperidinol, l-[3-(6-bromo-3-benzofuranyl)-propyl] -4-p-chlorophenyl-4-piperidinol, 4-p-chlorophenyl-l- [3-(6-methoxy-2-thianaphthenyl)propyl] -4-piperidinol, or 1-[3-(6-butoxy-2-benzofuranyl)propyl] -4-p-chlorophenyl-4-piperidinol, respectively.
Use of 4-p-fluorophenyl-4-piperidinol in the above the formation of 4-p-fluorophenyl-l-[3-(6-fluoro-3-thiana-phthenyl)propyl] -4-piperidinol.
EXAMPLE 8 4-Phenyl-l-[2-(3-thianaphthenyl)ethyl] -4-piperidinol A mixture of 15.0 g. (0.0824 moles) of thianaphthene-3-acetic acid [J. Am. Chem. Soc. 70, 3768 (1948)] and 30 ml. of SOCI2 is allowed to stand overnight at room temperature. The solution is diluted with benzene and evaporated in vacuo, and the procedure repeated. The residue is dissolved in ca. 500 ml. of dry toluene and 29.3 g. (0.165 moles) of 4-phenyl-4-piperidinol added. The mixture is stirred and refluxed for 2 hours, allowed to stand overnight at room temperature, and filtered. The filtrate is washed successively with dilute HC1, water, NaOH, and water, dried and evaporated in vacuo to give 4-phenyl-l- [2-(3-thianaphthenyl)acetyl] -4-piperidinol.
To a stirred mixture of 14.5 g. of LIAIH^ in 1 liter of dry ether is added slowly a solution of 26.3 g. (0.0824 moles) of the above amide in 100 ml. of dry tetrahydrofuran and 300 ml. of dry ether. The resulting mixture is refluxed for 2 hours, allowed to stand overnight at room temperature, and refluxed again for 2 hours. A total of ca. 60 ml. of water and 15 ml. of 10% NaOH is then added dropwise, the mixture stirred for one and one-half hours, and then filtered. The filtrate is washed with water and extracted with dilute HC1. The acidic and ethereal layers are filtered, and any solid obtained is dissolved in hot alcohol to which NaOH is added and this mixture then combined with the acidic extracts after they have been basified with NaOH. The total mixture is extracted with ether and the ethereal extracts washed, dried, and evaporated to give the title product. When the product is dissolved in alcohol and ethereal HC1 added, and then ether, alcohol-ether is obtained; m.p. 224-226°.
EXAMPLE 9 4-Phenyl-l-[4-(3- hianaphthenypbutylΊ -4-piperidinol To a stirred mixture of 78 g. of 57% NaH in mineral oil (44.5 g., 1.856 moles of NaH) in 1150 ml. of dry dimethyl sulfoxide, maintained in ice at 25-30°, is added dropwise a solution of 297 g. (1.856 moles) of diethyl malonate in 230 ml. of dimethyl sulfoxide. The resulting solution is stirred in a hot water bath at 50-60° for an hour and then cooled to room temperature, after which a solution of 170.0 g. (0.93 moles) of 3-chloromethylthianaphthene in 150 ml. of dr dimethyl sulfoxide is added dropwise. The resulting solution is heated on the steam bath for an hour, cooled, and poured into ice water. The mixture is extracted with ether, and the ethereal extracts washed, dried, and evaporated. The residue is distilled under vacuum, the fractions distilling at 123-232°/0.4 mm. being diethyl (3-thianaphthenylmethyl)malonate.
A solution of 200 g. of OH, 200 g. of water, and 131.2 g. (0.428 moles) of the above malonate in 2000 ml. of alcohol is stirred and refluxed for 4 hours and evaporated in vacuo. The residue is dissolved in water and washed with ether. The aqueous solution is cooled, acidified with concentrated HC1, and extracted with ether. The ethereal extracts are washed, dried, and evaporated in vacuo, and the residue triturated with hexane to give (3-thianaphthenyl)malonic acid, m.p. 170-171°dec.
The above malonic acid (17.5 g., 0.07 moles) is heated in an oil bath to ca. 250° and then at 230° for 1 hour. The melt is allowed to cool following the decarboxylation and 40 ml. of S0C12 added. After being allowed to stand benzene being added to the residue to eliminate traces of S0C12. The residue is the acid chloride of 3-(3-thianaphthenyl) propionic acid.
A solution of diazomethane is prepared as follows: To an unscratched 2 liter Erlenmeyer flask on a magnetic stirrer with a Teflon bar immersed in a salt-ice bath is added 75 ml. of 50% KOH and 200 ml. of ether. When the internal temperature of the mixture is below 0°, 29.4 g. (0.2 moles) of N-methyl-N'-nltro-N-nitrosoguanidine is added in small portions such that the internal temperature remains below 5°. The cold mixture is stirred in a salt-ice bath for 5 minutes and allowed to settle, and the ether solution decanted into an unscratched 2 1. Erlenmeyer flask containing KOH pellets and cooled in ice. The reaction mixture is extracted with 6-100 ml. portions of cold ether, the ether extracts dried in an ice bath with KOH pellets for one-half hour, and then filtered into an unscratched 2 liter filter flask in an ice bath, equipped with a magnetic stirrer. The solution is stirred in ice while a solution of 15.7 g. (0.07 moles) of the above acid chloride in a small amount of methylene chloride is added dropwise, nitrogen being evolved. The resulting solution is allowed to stand overnight, the ice bath being allowed to warm to room temperature and the solution is evaporated in vacuo using a hot water bath, a hood, and a safety shield, to leave as the residue l-diazo-4-(3-thia-naphthenyl)-2-butanone.
To a mixture of 14.0 g. (0.079 moles) of 4-phenyl-4-piperidlnol in ca. 300 ml. of dloxane which has been heated to achieve partial solution and then cooled to room temperature, is added a solution of 16.1 g. (0.07 moles) of the above diazoketone in 100 ml. of dioxane followed b 2.0 . of one-half hour, nitrogen being evolved. An additional 0.5 g. of Ag2<) is added, followed by heating at 60-70° for one-half hour and a final 0.5 g. portion of Ag20 added and heated.
The mixture is allowed to stand overnight at room temperature and then filtered through Super-Cel, and the filtrate evaporated in vacuo. The residue is dissolved in methylene chloride, and washed with acid, base, and water, and evaporated in vacuo to give 4-phenyl-l=[4-(3-thianaphthenyl)-butyryl]-4-piperidinol.
To a stirred mixture of 5.7 g. (0.15 moles) of LiAlH^ in 1000 ml, of dry ether is slowly added a solution of ca. 26 g. (0o07 moles) of the above amide in ca. 200 ml. of dry tetrahydrofuran. The resulting mixture is stirred and refluxed for 4 hours and then a total of ca. 25 ml. of water and 6 ml. of 10% NaOH added dropwise. The mixture is stirred for one-half hour and filtered. The filtrate is dried, charcoaled, filtered through Super-Cel, and evaporated in vacuo to give the title product, recrystallized from toluene; m.p. 126-131°. When the free base is dissolved in alcohol and ethereal HC1 added, a hydrochloride salt is formed; recrystallized from alcohol-ether; m.p. 183-186°.
EXAMPLE 10 l-[3-(2-Methyl-3-thianaphthenyl)propyl]-4-phenyl-4-piperidinol 2-Methyl-3-thianaphthenecarboxylic acid is reduced with LiAlH^ according to standard procedure to give 3-hydroxymethyl-2-methylthianaphthene. The hydroxymethyl group is converted to chloromethyl with SOCI2 as described in Procedure 1 and the product condensed with diethyl malonate as in Example 1. By following the rest of the steps of Example 1, including hydrolysis, decarboxylation, formation of the ester anh dride and then the amide, and finall EXAMPLE 11 When 5»chloro~3-methylbenzofuran<-2»acetic acid and 5-methoxy-2-methylbenzofuran-3»acetic acid are substituted for the thianaphthene<»3~acetic acid in the procedure of Example 8, and the acid chloride formation, amide formation, and reduction carried out as described therein, 1- [ 2- (5->chloro-3=methyl-2-benzofuranyl)ethyl]-4-phenyl-4-piperidinol and l[2-(5-methoxy-2-methyl-3-benzofuranyl)ethyl]=4=phenyl-4=piperidinol, respectively* are obtained.
When 6-methoxy=3-benzofuranbutyric acid and 5= methoxy-3-thianaphthenebutyric acid are substituted for the thianaphthene-3-acetic in the procedure of Example 8, and the acid chloride formation, amide formation, and reduction carried out as described therein, l-[4-(6°methoxy=3°benzofuranyl)-butyl] -4-phenyl-4=piperidinol and l-[4-(5-methoxy-3-thianaphthenyl)butyl]-4-phenyl-4-piperidinol, respectively, are obtained.
EXAMPLE 12 A tablet may have the following composition: 4-phenyl-l-[3-(3-thianaphthenyl)propyl]«4- 10 mg. piperidinol hydrochloride magnesium stearate 2.5 mg. starch 15 mg. terra alba 150 mg. granulate with syrup or 5% gelatin solution terra alba q.s. ad 300 mg.
An injectable solution may have the following composition per cc: 4=phenyl-l-[3-(2-thianaphthenyl)propyl]-4- 5 mg. piperidinol hydrochloride sodium biphosphate 5 mg. sodium tartrate 12 mg.
EXAMPLE 13 4-Phenyl-l-[3-(3-thianaphthenyppropyl1-4-plperidlnol O-acetate A solution of 4.2 g. (0.012 moles) of 4-phenyl-l-[3-(3-thianaphthenyppropyl] -4-piperidinol and 2 or 3 drops of cone. I^SO^ in 100 ml. of acetic anhydride is stirred on the steam bath for 3 hours and evaporated in vacuo. The residue is warmed and stirred with 5% then cooled, and methylene chloride added. The layers are separated and the aqueous layer washed with methylene chloride. The organic extracts are washed, dried, and evaporated in vacuo to give the title product. This free base is dissolved in alcohol, ethereal hydrogen chloride added, and the ether is added. Filtration gives the hydrochloride salt of the title product, which is triturated with ethyl acetate and recrystallized from isopropanol-ether ; m.p. 173-175°.
EXAMPLE 14 4-Phenyl-l-[3-(3-thianaphthenyppropyl] -4-piperidinol 0-propionate A 7.5 g. (0.0193 moles) sample of 4-phenyl-l-[3-(3-thianaphthenyppropyl] -4-piperidinol hydrochloride is converted to the free base and dissolved in 250 ml. of dry benzene. A solution of 1.8 g. (0.0193 moles) of propionyl chloride in 50 ml. of dry benzene is added, and the cloudy solution is stirred and refluxed for 1 hour and allowed to stand at room temperature overnight. The mixture is filtered and the filtrate evaporated in vacuo to give the title product. The base is dissolved in alcohol, ethereal hydrogen chloride added, and the mixture then diluted with ether. The hydrochloride salt of the title product is filtered off and recrystallized from alcohol-ether; m.p. 177-179°.
SXAIIPLE 15 1, l-Dloxide-3-thlamphthenyl)propyl- phen l-^-piperldlnol A solution of Jt*64g* (0*012 moles) of 4-phenyl-l- ~3-(3-thlanaphthenyl) ropyl7-^-plperldlnol hydrochloridef 40 ml* of glacial acetic acid, and 12 ml. of 30$ HgOg is heated at 60° for 1 hour* The mixture is stirred and refluxed for 15 minutes then diluted with ice water , made alkaline with MaOH, and extracted with methylene chloride* The organic extracts are 1 washed, dried, and concentrated to give the title product.
Addition of hydrogen chloride to an isopropanol solution of the product, followed by ether gives the hydrochloride salt; m.p. 228.5-230°.
When the following thianaphthene compounds are oxidized according to the above procedure, the corresponding listed sulfones are obtained.
Thianaphthene 1- [3-(5-chloro-2-thianaphthenyl)propyl]-4-phenyl=4-piperidinol 10 4-phenyl-l-[ 3- (2-thianaphthenyl)propyl] -4-piperidinol 4-phenyl-l-[ 2- (3-thianaphthenyl)ethyl] -4-piperidinol 4-phenyl-l- [4-(3-thianaphthenyl)butylJ-4-piperidinol Sulfone 1-[ 3- (5-chloro-l, l-dioxer™2-thianaphthenyl)propyl] -4«phenyl-4-J5 piperidinol 1- [ 3-(1, l-dioxp-2-thianaphthenyl)propyl] ~ - henyl- -piperidinol l-[2-(l,l-diox ¾-thianaphthenyl)ethyl]-4-phenyl=4-piperidinol l-[4-(l,l-dioxe^-thianaphthenyl)butyl]-4-phenyl-4-piperidinol Procedure 1 5-Chloro-2-chloromethylthianaphthene Dry ether (50 ml.) is added slowly to a cooled solution of 7.925 g. (0.124 moles) of butyl lithium in 80 ml. of hexane under nitrogen. The cooled solution is stirred, a solution of 16.8 g. (0.1 moles) of 5-chlorothianaphthene in 50 ml. of dry ether is added slowly, and the resulting solution is stirred in ice for 2 hours. A 9.5 g. (0.32 moles) sample of paraformaldehyde (dried by heating on the steam bath for 2 hours in vacuo) is placed in an oil bath at about 190°, and the formaldehyde is swept into the reaction mixture with 3Q nitrogen. After addition is complete (ca. 1 hour), the mixture to destroy the remaining butyl lithium and then with ca. 200 ml. of aqueous salt solution. The layers are separated, the aqueous layer is washed with ether, and the combined ethereal extracts are washed, dried, and evaporated in vacuo to give a solid. Trituration with petroleum ether and recrystallization from toluene gives 5-chloro-2-hydroxymethylthianaphthene, m.p. 122-124.5°.
To a stirred solution of 13.0 g. (0.0655 moles) of this compound in 100 ml. of chloroform is added dropwlse 12.0 ml. of S0C12. The resulting mixture is stirred and refluxed for a half hour and then evaporated in vacuo. The residue is dissolved in benzene and again evaporated to give the title compound.
-Chlorothianaphthene, as well as the 5, 6, and 7-methylthianaphthenes, is described in Chemical Abstracts 47, 12346 gh.
Claims (15)
1. HAVING NOW paxticularly described and ascertained the nature of our said invention and in what manner the same is to be performed, we declare that what we claim is s - 1. A compound of the formula or a pharmaceutically acceptable acid addition salt thereof, wherein: R is at the 5 or 6-position and is hydrogen, chloro, bromo, fluoro, trifluoromethyl, lower alkyl of 1-4 carbon atoms, or lower alkoxy of 1-4 carbon atoms; R^" is hydrogen, chloro, bromo, methyl, trifluoromethyl, fluoro, or methoxy; 2 R is hydrogen or methyl; 3 R is hydrogen or lower alkanoyl of up to 6 carbon atoms ; Y is oxygen, sulfur, or sulfone; and n is a positive integer from 2 to 4. 2
2. A compound as claimed in claim 1, where R is hydrogen.
3. as claimed in claim 2, where n is 3.
4. as claimed in claim 3, where Y is sulfur.
5. A compound as claimed in claim 4, where R is hydrogen, chloro, or fluoro; R is at the p-position and is 3 hydrogen, chloro, or fluoro; and R is hydrogen.
6. A compound as claimed in claim 5, where R and R^ are both hydrogen, being the compound 4-phenyl-l-[3-(3-thiana-phthenyl)propyl]-4-piperidinol or its hydrochloride salt.
7. A compound as claimed in claim 5, where R and R" are both hydrogen, being the compound 4-phenyl-l-[3-(2-
8. A compound as claimed in claim 5, where R is 5-chloro and is hydrogen, being the compound l-[3-(5-chloro 2-thianaphthenyl)propyl]-4-phenyl-4-piperidinol or its hydrochloride salt.
9. A compound as claimed in claim 5, where R is hydrogen and R^" is chloro, being the compound 4-p-chlorophenyl l-[3-(3-thianaphthenyl)propyl]-4-piperidinol or its hydrochloride salt.
10. A compound as claimed in claim 2, where R is hydrogen, R^" is p-methyl, n is 3, and Y is sulfur, being the compound l-[3-(3-thianaphthenyl)propyl]-4=p-tolyl-4-piperidino or its hydrochloride salt.
11. , A compound as claimed in claim 2, where R is hydrogen, J* is p-trifluoromethyl, n is 3, and Y is sulfur, being the compound l-[3-(3-thianaphthenyl)propyl]-4-p-trifluoromethylphenyl-4-piperidinol or its hydrochloride, salt.
12. A compound as claimed in claim 5, where R and R^" are both chloro, being the compound 4-p-chlorophenyl-l- [3-(6-chloro-3-thianaphthenyl)propyl] -4-piperidinol or its hydrochloride salt.
13. A compound as claimed in claim 5, where R is 6-fluoro and R^ is chloro, being the compound 4-p-chlorophenyl l-[ 3-(6-fluoro-3-thianaphthenyl)propyl] -4-piperidinol or its hydrochloride salt.
14. A compound as claimed in claim 2, where R and R^ are hydrogen, n is 2, and Y is sulfur, being the compound 4-phenyl-l-[ 2- (3-thianaphthenyl)ethyl] -4-piperidinol or its hydrochloride salt.
15. A compound as claimed in claim 2, where R and R are hydrogen, n is 4, and Y is sulfur, being the compound 4-phenyl-l-[4-(3-thianaphthenyl)butyl] -4-piperidinol or its 2k* Substituted plperidlnoalkyl benzo (b) thlophenes and benzofurans as defined In claim 1 and pharmaceutical compositions containing these as active ingredient, substantially as hereinbefore described and with reference to any of the examples· For Applicants:
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US62062867A | 1967-03-06 | 1967-03-06 | |
US66970767A | 1967-09-22 | 1967-09-22 |
Publications (1)
Publication Number | Publication Date |
---|---|
IL29437A true IL29437A (en) | 1971-11-29 |
Family
ID=27088751
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
IL29437A IL29437A (en) | 1967-03-06 | 1968-02-08 | Substituted piperidinoalkyl benzo (b)thiophenes and benzofurans |
Country Status (6)
Country | Link |
---|---|
DK (1) | DK120387B (en) |
ES (1) | ES350880A1 (en) |
FI (1) | FI50422C (en) |
IE (1) | IE32098B1 (en) |
IL (1) | IL29437A (en) |
SE (1) | SE342040B (en) |
-
1968
- 1968-02-08 IL IL29437A patent/IL29437A/en unknown
- 1968-02-09 DK DK51668AA patent/DK120387B/en unknown
- 1968-02-23 IE IE218/68A patent/IE32098B1/en unknown
- 1968-02-24 ES ES350880A patent/ES350880A1/en not_active Expired
- 1968-03-01 FI FI680559A patent/FI50422C/en active
- 1968-03-05 SE SE2863/68A patent/SE342040B/xx unknown
Also Published As
Publication number | Publication date |
---|---|
SE342040B (en) | 1972-01-24 |
ES350880A1 (en) | 1969-05-16 |
FI50422B (en) | 1975-12-01 |
DK120387B (en) | 1971-05-24 |
FI50422C (en) | 1976-03-10 |
IE32098B1 (en) | 1973-04-18 |
IE32098L (en) | 1968-09-06 |
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